In traditional sustained release matrix systems, the drug is incorporated into a matrix consisting of either hydrophobic or hydrophilic materials such as polymers. The predominant mechanism of drug release from such systems is diffusion, resulting in curved release profiles that can be described by square root of time kinetics. Such release profiles are characterized by initial rapid release followed by a gradual decline in the rate of release, resulting in a prolonged “tailing off” in the late time phase. This “tailing off” is often accompanied by incomplete dissolution. Furthermore, there is typically an initial rapid release described as a “burst effect” which is attributed to the initial rapid wetting and dissolution of drug on the surface of the dosage form. This type of curved release profile may be a disadvantage for drugs that are to be absorbed throughout the gastrointestinal tract over an extended period of time at a controlled or constant rate. More specifically, the amount of drug available for absorption, over a period of drug release, steadily decreases. This may necessitate more frequent dosing compared to a dosage form that has a more linear drug release profile over an extended period of time. However, even in formulations that have a near zero order release, burst effects are frequently seen. The burst effect can be expected to be especially problematic as drug load increases, because by implication the concentration of drug at the tablet surfaces increases.
A number of approaches have been adopted to counteract the natural diffusive processes which control mass transfer from compressed tablets into surrounding aqueous dissolution media and to limit the burst effect. In particular, several methods to achieve so-called “zero order” controlled release or constant rates of release and approximate linear release profiles have been developed. These approaches include geometric modifications of the tablet, resulting in control of the surface area available for drug diffusion. Other examples include the use of multiple layer tablets, osmotic pumps, and coated pie shaped and hemispherical tablets with strategically located un-coated portions of surface area.
Many of the above named systems are of great utility, however they suffer shortcomings in that they are relatively costly and complicated to manufacture, often requiring multiple manufacturing steps and specialized equipment.
In addition, osmotic pump systems and multiple layer systems tend to deliver the drug in linear fashion only to about 85% of the total drug loaded, with severe tailing off thereafter. In the case of oral osmotic systems, this effect may be ascribed to the exhaustion of the reservoir device and the loss of osmotic pressure. Also, the aforementioned devices are of limited usefulness for the controlled delivery of large doses of medicament, for example more than 600 mg., especially if the medicament is relatively water soluble. In such cases of high drug loading, the addition of an absolute minimum of rate controlling excipient is necessary to achieve a tablet size that can be comfortably swallowed. Additionally, the need to add relatively large amounts of osmoagent and/or hydrophilic rate controlling swelling polymer layers severely limits the maximum drug load achievable in such systems.
Thus there is a need for a simple monolithic matrix tablet that is capable of delivering a high drug load irrespective of drug solubility to approximate zero order release kinetics.
In recent years, the value of hydrophilic polymer based systems employing controlled release has been increasingly demonstrated with the publication of numerous patents and research papers. Infield et al., U.S. Pat. No. 5,393,765, describes a hydrophilic erodible monolithic tablet formulation capable of approximating zero order drug release based on hydroxypropylmethyl cellulose and various erosion enhancing excipients such as lactose and surfactants such as Pluronic®. These constituents are mixed with a drug to form a matrix, and subsequently tableted. When ingested, the Infield et al. matrix forms two layers, an outer layer of hydrated matrix and an inner layer of unchanged matrix.
While semi-synthetic cellulose derivatives have found wide use in controlled release formulations, a number of polysaccharide based excipients have also been employed in oral controlled release systems. Polysaccharides which have been used as controlled release excipients, and have been employed on their own or in combination with other excipients, include chitosan, alginic acid, carrageenan, scleroglucan, and modified starch products.
Xanthan gum, a semi-synthetic polysaccharide of bacterial origin, has also received frequent attention as a controlled release material. The potential of xanthan gum alone has been evaluated, and a number of studies of xanthan gum in combination with alginic acid or guar gum have also been published. Baichwal et al., U.S. Pat. Nos. 4,994,276, 5,128,143, and Staniforth et al., U.S. Pat. No. 5,135,757, disclose controlled release excipient systems utilizing xanthan gum and a synergistically interacting polysaccharide such as locust bean gum or guar gum, along with secondary and tertiary components such as saccharides or other hydrophilic polymers. In these patents, it is speculated that a synergistic interaction occurs between xanthan and the polysaccharide gum resulting in an increased viscosity and gel strength. Based on similar principles of a synergistic interaction between xanthan and a gum, Baichwal, et al., U.S. Pat. No. 5,455,046, discloses a sustained release dosage form suitable for insoluble drugs such as nifedipine by employing cross-linked heteropolysaccharides and polysaccharides.
Guar, a natural galactomannan, obtained from the seeds of Cyanopsis tetragonolobus has found use in the pharmaceutical industry as a disintegrating and binding agent for tablets, as well as a suspending, thickening, and stabilizing agent for liquid and semi solid products. Guar gum has also been used in some extended release formulations and combinations of xanthan gum and guar gum have been extensively studied. The studies indicate that in certain instances, large amounts of hydroxypropylmethyl cellulose had to be added to guar gum to achieve acceptable sustained release formulations. Altaf et al. (1998 ) and Yu et al. (1998) published articles on a guar gum based sustained release formulation containing diltiazem which was shown to be equivalent in vitro and in vivo to a commercial product (Dilacor XR®). However, neither of these two preparations achieved a predominantly zero order release profile. Khurts, in U.S. Pat. No. 5,292,518, discloses prolonged release formulations consisting of gel forming dietary fiber, such as guar gum, a drug, a mineral salt, which releases a physiologically acceptable gas on ingestion, disintegrants and binders. Optionally, organic acids such as maleic and citric acid can be included to further aid disintegration.
Furthermore, guar gum has been found to undergo efficient enzymatic degradation in the human large intestine and has therefore been used as a carrier for colon specific drug delivery. Modifying guar gum with borax or glutaraldehyde has been reported as an effective means of producing cross linked polymers with limited swelling potential and increased viscosity. The limited swelling and increased viscosity reportedly increases the potential for the polymer matrix to stay intact and release a minimum of drug until the colon is reached. Friend and Wong, U.S. Pat. No. 5,811,388, disclose a simple formulation consisting of a drug useful for treating colonic disorders or a peptide drug that can be absorbed from the colon, and a hydrocolloid gum obtainable from higher plants, preferably guar gum. The authors mention the possible inclusion of a host of substances that may serve to stabilize a peptide or protein drug, or aid in drug penetration of gastrointestinal membranes and absorption.
Amino acids such as glycine find frequent use as plasticizers in polymer film coatings, as buffering agents and excipients used in the stabilization and formulation of lyophilized products, injectables, nose drops and oral solutions. For example, DL-leucine has been used as a hydrophilic lubricant. Ibsen, U.S. Pat. No. 5,288,500, discloses the possible use of amino acids in combination with hydrophilic polymers to enhance rapid swelling in order to mask grittiness and taste in formulations of granules that are to be rapidly dispersed in water prior to ingestion. Adesunloye, U.S. Pat. No. 5,874,106, discloses that amino acids in combination with carboxylic acids such is as citric acid, prevent cross-linking in gelatin capsules. Finally, Thombre et al., U.S. Pat. No. 5,697,922, describe an osmotic device wherein solubility adjusting substances, which may simultaneously act as osmoagents, can be made into coated macro particles. These solubility adjusting substances may include ionizing substances, salts, surfactants or amino acids.
Though useful as dosage forms, the release profiles of many of the prior compositions are usually characterized by initial rapid release followed by a gradual decline in the rate of release, resulting in a “prolonged tailing off” in the late time phase. The “tailing off” often results in incomplete dissolution and failure to achieve 100% drug release. Furthermore, there is typically an initial “burst effect”, causing a relatively large amount of drug to be released early in dissolution, which is attributed to the initial rapid wetting and dissolution of drug on the surface of the dosage form. Lastly, many such systems suffer practical shortcomings in that they are relatively costly and complicated to manufacture, often requiring multiple manufacturing steps and specialized equipment.
Kim et al., WO 99/21551, discloses a simple polymeric matrix tablet that is designed to deliver drugs over extended periods of time, while being relatively easy to manufacture. The drug is first granulated with a swellable polymer to form granules. The granules are then dispersed within a matrix of a more swellable, erodible polymer and compressed to form a monolithic matrix tablet which is readily manufactured on commercial high speed tabletting equipment. Kim et al. does not make use of amino acids to mediate polymer swelling and dissolution of the drug, and the solubility of the drug plays the greatest role in determining the release profile and release duration. Therefore, Kim et al. is limited in application to highly soluble drugs.
The present invention provides an extended release dosage form for simple monolithic matrix tablets capable of delivering a high drug load of pharmaceutically active substances according to zero order release kinetics over an extended period of time, preferably 12 to 24 hours, in which drug release is mediated by the inclusion of an amino acid.
Definitions
As used herein the following terms have the definitions set forth below.
“Hydropathy” refers to a scale of solubility characteristics combining hydrophobicity and hydrophilicity of amino acids. More particularly this term refers to a sliding scale, similar to a pH scale, which assigns relative values which represent the relative balance between hydrophobic and hydrophilic components of an amino acid. A typical scale is set forth in Pliska et al., J. Chromatog. 216, 79, 1981, entitled Relative Hydrophobic Character of Amino Acid Side Chains, wherein glycine has a value of 0, representing a relatively equal balance between hydrophobic and hydrophilic components and may be referred to as relatively ‘neutral’, ‘balanced’, ‘slightly hydrophilic’; or ‘weakly hydrophobic’, iso-leucine has a positive value of 1.83 and is strongly hydrophobic, and on the opposite end of the scale, aspartic acid has a negative value of −2.15 and may be characterized as strongly hydrophilic. Such a scale and the hydropathy characteristics described herein are well known and understood by those skilled in the art. Representative values and hydropathy characteristics are set forth in Table 1.
“Monolithic” refers to tablets that do not require multiple layers, special shapes, osmotic compartments and/or specialized coatings, typically without joints or seams, and are capable of being tableted on modern high speed tableting equipment.